This is a U.S. patent application being filed under 37 C.F.R. 1.53(b) claiming priority to GB9921396.9 filed Sep. 11, 1999 in the United Kingdom; for which GB0014451.9 was filed Jun. 13, 2000 and GB0018654.4 was filed Jul. 28, 2000 in the United Kingdom.
1. Field of the Invention
The present invention relates to a pharmaceutical formulation for use in the administration of medicaments by inhalation. In particular, this invention relates to a pharmaceutical formulation of fluticasone propionate for use in metered dose inhalers (MDI""s). The invention also relates to methods for their preparation and to their use in therapy.
2. Description of the Background Art
Inhalers are well known devices for administering pharmaceutically active materials to the respiratory tract by inhalation. Such active materials commonly delivered by inhalation include bronchodilators such as xcex22 agonists and anticholinergics, corticosteroids, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
(6a,11b,16a,17a)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy) androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester was described as an anti-inflammatory steroid by U.S. Pat. No. 4,335,121. This compound is also known by the generic name of fluticasone propionate and has since become widely known as a highly effective steroid in the treatment of inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD).
Metered dose inhalers (MDI""s) are the most common type of a wide range of inhaler types and utilise a liquefied propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. MDI formulations are generally characterised as solution formulations or suspension formulations.
The most commonly used aerosol propellants for medicaments have been Freon 11 (CCl3F) in admixture with Freon 12 (CCl2F2) and Freon 114 (CF2Cl.CF2Cl). However, these propellants are now believed to provoke the degradation of stratospheric ozone and their use is now being phased out to eliminate the use of all CFC containing aerosol propellants. There is thus a need to provide an aerosol formulation for medicaments which employ so called xe2x80x98ozone-friendlyxe2x80x99 propellants.
Hydrofluoroalkanes (HFAs; known also as hydrofluorocarbons or HFCs) contain no chlorine and are considered less destructive to ozone and these are proposed substitutes for CFCs. In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants.
The efficiency of an aerosol device, such as an MDI, is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterised by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
Particle deposition in the lung depends largely upon three physical mechanisms:
1. impaction, a function of particle inertia;
2. sedimentation due to gravity; and
3. diffusion resulting from Brownian motion of fine, submicrometer ( less than 1 xcexcm) particles.
The mass of the particles determines which of the three main mechanisms predominates.
The effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacements produced by diffusion decrease. In practice, diffusion plays little part in deposition from pharmaceutical aerosols. Impaction and sedimentation can be assessed from a measurement of the MMAD which determines the displacement across streamlines under the influence of inertia and gravity, respectively.
Aerosol particles of equivalent MMAD and GSD (geometric standard deviation) have similar deposition in the lung irrespective of their composition. The GSD is a measure of the variability of the aerodynamic particle diameters.
For inhalation therapy there is a preference for aerosols in which the particles for inhalation have a diameter of about 0.5 to 5 xcexcm. Particles which are larger than 5 xcexcm in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5 xcexcm in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3 xcexcm in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 xcexcm may be exhaled.
Respirable particles are generally considered to be those with aerodynamic diameters less than 5 xcexcm. These particles, particularly those with a diameter of about 3 xcexcm, are efficiently deposited in the lower respiratory tract by sedimentation.
It has been recently demonstrated in patients with mild and severe airflow obstruction that the particle size of choice for a xcex22 agonist or anticholinergic aerosol should be approximately 3 xcexcm (Zaanen, P. et al, Int. J. Pharm. (1994) 107, 211-217, Int. J. Pharm. (1995) 114, 111-115, Thorax (1996), 51, 977-980.)
Many of the factors relevant to the MMAD of particles are relevant to droplets and the additional factors of rate of solvent evaporation, and surface tension are also important.
In suspension formulations, particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation. However, if the suspended drug has the slightest solubility in propellant, a process known as Ostwald Ripening can lead to particle size growth. Also, particles may have tendency to aggregate, or adhere to parts of the MDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particularly severe for potent drugs (including fluticasone propionate) which need to be formulated in low doses. Solution formulations do not suffer from these disadvantages, but suffer from different ones in that particle or droplet size is both a function of rate of evaporation of the propellant from the formulation, and of the time between release of formulation from canister and the moment of inhalation. Thus, it may be subject to considerable variability and is generally hard to control.
Besides its impact on the therapeutic profile of a drug, the size of aerosol particles has an important impact on the side effect profile of a drug. For example, it is well known that the orthopharynx deposition of aerosol formulations of steroids can result in side effects such as candidiasis of mouth and throat. Accordingly, throat deposition of such aerosol formulations is generally to be avoided. Furthermore, a higher systemic exposure to the aerosol particles due to deep lung penetration can enhance the undesired systemic effects of certain drugs. For example, the systemic exposure to certain steroids can produce side effects on bone metabolism and growth.
Thus, according to the present invention we provide a pharmaceutical aerosol formulation for use in a metered dose inhaler, comprising (i) fluticasone propionate and (ii) a hydrofluoroalkane (HFA) propellant; and characterised in that the fluticasone propionate is completely dissolved in the formulation.
The formulation according to the invention will generally contain a solubilisation agent to aid solubilisation of the fluticasone propionate in the formulation. Suitable solubilisation agents include propylene glycol and ethanol, preferably ethanol. Other suitable solubilisation agents include ethers (eg dimethyl ether). Alkanes may also be of use. A further solubilisation agent of interest is dimethoxymethane (methylal) which has good solvency properties. We have also found ethylacetate to be a solubilising agent with good solvency properties.
As a particular aspect of the present invention we provide a pharmaceutical aerosol formulation comprising (i) fluticasone propionate, (ii) a hydrofluoroalkane (HFA) propellant, (iii) a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler and (iv) a solubilisation agent in sufficient quantity to solubilise the fluticasone propionate in the formulation.
The presence of the low volatility component in the solution formulation increases the fine particle mass (FPM) as defined by the content of stages 3-5 of an Andersen Cascade Impactor on actuation of the formulation relative to solutions formulations which omit this component. Solution formulations which omit the higher volatility component generally give rise to a particle size distribution which have a higher content of finer particles; such distributions generally do not match the distribution of the existing commercialised suspension formulations which contain CFC""s and may therefore not be bio-equivalent.
Examples of HFA propellants include 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) and mixtures there of. The preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a). An alternative propellant of interest is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).
The preferred low volatility component is glycerol, propylene glycol or polyethyleneglycol (eg PEG 200 or PEG 400), especially glycerol. Polyethylene glycol is also of particular interest, especially PEG400. Preferably it is present in an amount of 0.5 to 3% (w/w), especially around 1% (w/w).
The preferred solubilisation agent is ethanol.
More specifically, the present invention can be defined as a pharmaceutical aerosol formulation which comprises:
(i) fluticasone propionate;
(ii) 1,1,1,2-tetrafluoroethane (HFA 134a);
(iii) 0.5-3% (w/w) glycerol; and
(iv) a solubilisation agent (particularly ethanol) in sufficient quantity to solubilise the fluticasone propionate in the formulation.
We prefer the formulation to be suitable for delivering a therapeutic amount of fluticasone propionate in one or two actuations. Preferably, the formulation will be suitable for delivering 25-250 xcexcg per actuation, especially 25 xcexcg, 50 xcexcg, 125 xcexcg or 250 xcexcg per actuation. However, as mentioned in the foregoing, the amount of ethanol required to dissolve high concentrations of fluticasone propionate may tend to depress the vapour pressure of the propellant to an undesirable degree. The vapour pressure should desirably remain above around 50 psi. Therefore the formulation is most suitable for delivering 25-125 xcexcg per actuation, especially 25-50 xcexcg per actuation.
The formulation according to the invention will be used in association with a suitable metering valve. We prefer that the formulation is actuated by a metering valve capable of delivering a volume of between 50 xcexcl and 100 xcexcl, eg 50 xcexcl or 63 xcexcl. 100 xcexcl is also suitable. When a 50 xcexcl metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.1% w/v (which equates to 0.1 g of fluticasone propionate per 100 ml of formulation) or approx. 0.083% w/w (which equates to 0.083 g of fluticasone propionate per 100 g of formulation) for a 50 xcexcg dose, 0.25% (w/v) or approx. 0.21% (w/w) for a 125 xcexcg dose, 0.5% (w/v) or approx. 0.42% (w/w) for a 250 xcexcg dose and 0.05% (w/v) or approx 0.042% (w/w) for a 25 xcexcg dose. Wherein a 63 xcexcl metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.079% (w/v) or approx. 0.067% (w/w) for a 50 xcexcg dose, 0.198% (w/v) or approx. 0.167% (w/w) for a 125 xcexcg dose, 0.397% (w/v) or approx. 0.333% (w/w) for a 250 xcexcg dose and 0.04% (w/v) or approx. 0.033% (w/w) for a 25 xcexcg dose. When a 100 xcexcl metering volume is used, the final concentration of fluticasone propionate delivered per actuation would be 0.05% w/v (which equates to 0.05 g of fluticasone propionate per 100 ml of formulation) or approx. 0.042% w/w (which equates to 0.042 g of fluticasone propionate per 100 g of formulation) for a 50 xcexcg dose, 0.125% (w/v) or approx. 0.11% (w/w) for a 125 xcexcg dose, 0.25,% (w/v) or approx. 0.21% (w/w) for a 250 xcexcg dose and 0.025% (w/v) or approx 0.021% (w/w) for a 25 xcexcg dose. The previously quoted w/w figures are approximate in that they do not compensate in the mismatch in density between HFA134a and ethanol, however the precise figures may be readily determined.
The formulation is most suitable for concentrations of fluticasone propionate in the range 0.025 to 0.25% (w/v), preferably 0.025 to 0.15% (w/v), more preferably 0.035 to 0.15% (w/v), particularly 0.04 to 0.1% (w/v). A concentration of 0.025 to 0.04% (w/v) is also of particular interest. Formulations of the present invention containing such low concentrations of fluticasone propionate may have particular physical stability advantages relative to suspension formulations containing the same wherein particles of fluticasone propionate may be susceptible to Ostwald ripening or to drug deposition on the canister wall or on parts of the valve as discussed above. Drug deposition is especially problematic in low strength fluticasone propionate suspension formulations because the amount of drug lost through deposition on internal surfaces of the metered dose inhaler can represent a significant proportion of the total available drug and therefore have a significant effect on dosing uniformity through the life of the product. The solution formulations of the present invention overcome or substantially mitigate such disadvantages.
Use of a larger metering chamber eg 100 xcexcl will generally be preferred.
We prefer the formulation to contain between 0.5 and 2% w/w, more preferably between 0.8 and 1.6% w/w, particularly between 1.0 and 1.6% w/w glycerol. Another range of particular interest is 0.5-1% (w/w) glycerol. We especially prefer to use 1.3% (w/w) glycerol. We also especially prefer to use 1.0% w/w glycerol.
Depending on the final concentration of fluticasone propionate in the formulation, the propellant, and the precise amount of low volatility component, the concentration of solubilisation agent (eg ethanol) required will vary. So as not to suppress the vapour pressure of the propellant to an undesirable extent, the amount of ethanol should preferably not exceed around 35%. The amount of ethanol will more preferably be in the range 5 to 30%, particularly 5 to 20%, more particularly 10 to 20%. A range of 7 to 16% w/w is also particularly preferred, more particularly 7 to 11% w/w.
When the concentration of fluticasone propionate is around 0.1% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 16-24% w/w eg 16-18% w/w, especially around 16% w/w is particularly suitable but is more preferably 20-22% w/w especially around 21% w/w. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 7-11% w/w eg 7-8% w/w, especially around 7% w/w is particularly suitable but is more preferably 9-11% w/w especially around 10% w/w. When the concentration of fluticasone propionate is around 0.079% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 15-17% w/w especially around 16% is suitable. When the concentration of fluticasone propionate is around 0.198% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 34-36% w/w eg around 35% is suitable. When the concentration of fluticasone propionate is around 0.025% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethanol of 7-9% w/w especially around 8%, more preferably around 7% is suitable.
When the concentration of fluticasone propionate is around 0.025% w/v and the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount of ethanol of 13-15% w/w especially around 14% is suitable. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2,3,3,3-heptafluoro-n-propane, an amount of ethanol of 17-19% w/w especially around 18% is suitable.
When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of ethylacetate as solubilisation agent of 13-16% w/w especially around 15% is suitable. When the concentration of fluticasone propionate is around 0.05% w/v and the propellant is 1,1,1,2-tetrafluoroethane, an amount of dimethoxymethane (methylal) as solubilisation agent of 13-16% w/w especially around 15% is suitable.
The above generally described formulations are particularly preferred in conjunction with 1.0-1.6% w/w glycerol, particularly 1.0% w/w glycerol or 1.3% w/w glycerol.
Formulations according to the invention which are free of surfactants are preferred. Formulations according to the invention which are free of all excipients besides the solubilisation agent (eg ethanol), low volatility component (such as glycerol) and the propellant are particularly preferred.
Formulations according to the invention will preferably contain fluticasone propionate as the only medicament. However formulations which contain medicaments in addition to fluticasone propionate such as beta adrenergic agonists and anti-cholinergic compounds may also be contemplated.
The pharmaceutical composition according to the present invention may be filled into canisters suitable for delivering pharmaceutical aerosol formulations. Canisters generally comprise a container capable of withstanding the vapour pressure of the HFA propellant, such as plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. It may be preferred that canisters be coated with a fluorocarbon polymer as described in WO 96/32151, for example, a co-polymer of polyethersulphone (PES) and polytetrafluoroethylene (PTFE). Another polymer for coating that may be contemplated is FEP (fluorinated ethylene propylene). The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Thermoplastic elastomer valves as described in WO92/11190 and valves containing EPDM rubber as described in WO95/02651 are especially suitable. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (eg. DF10, DF30, DF60), Bespak plc, UK (eg. BK300, BK356, BK357) and 3M-Neotechnic Ltd, UK (eg. Spraymiser(trademark)). The DF31 valve of Valois, France is also suitable.
Valve seals, especially the gasket seal, and also the seals around the metering chamber, will preferably be manufactured of a material which is inert to and resists extraction into the contents of the formulation, especially when the contents include ethanol.
Valve materials, especially the material of manufacture of the metering chamber, will preferably be manufactured of a material which is inert to and resists distortion by contents of the formulation, especially when the contents include ethanol. Particularly suitable materials for use in manufacture of the metering chamber include polyesters eg polybutyleneterephthalate (PBT) and acetals, especially PBT.
Materials of manufacture of the metering chamber and/or the valve stem may desirably be fluorinated, partially fluorinated or impregnated with fluorine containing substances in order to resist drug deposition.
Valves which are entirely or substantially composed of metal components (eg Spraymiser, 3M-Neotechnic) are especially preferred for use according to the invention.
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The medicament is added to a charge vessel and a mixture of ethanol, low volatility component and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel. An aliquot of the formulation is then filled through the metering valve into the canister. Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
In an alternative process, an aliquot of the liquified formulation is added to an open canister under conditions which are sufficiently cold that the formulation does not vaporise, and then a metering valve crimped onto the canister.
In an alternative process an aliquot of medicament dissolved in the solubilising agent and any low-volatility component is dispensed into an empty canister, a metering valve is crimped on, and then the propellant is filled into the canister through the valve.
Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channelling devices comprise, for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient eg. a mouthpiece actuator.
In a typical arrangement the valve stem is seated in a nozzle block which has an orifice leading to an expansion chamber. The expansion chamber has an exit orifice which extends into the mouthpiece. Actuator (exit) orifice diameters in the range 0.15-0.45 mm particularly 0.2-0.45 mm are generally suitable eg 0.15, 0.22, 0.25, 0.30, 0.33 or 0.42 mm. We have found that it is advantageous to use a small diameter eg 0.25 mm or less, particularly 0.22 mm since this tends to result in a higher FPM and lower throat deposition. 0.15 mm is also particularly suitable. The dimensions of the orifice should not be so small that blockage of the jet occurs.
Actuator jet lengths are typically in the range 0.30-1.7 mm eg 0.30, 0.65 or 1.50 mm. Smaller dimensions are preferred eg 0.65 mm or 0.30 mm.
Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or xe2x80x98puffxe2x80x99, for example in the range of 25 to 250 xcexcg medicament per puff.
Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. Treatment may be of asthma, chronic obstructive pulmonary disease (COPD) or other respiratory disorder. It will be appreciated that the precise dose administered will depend upon the age and condition of the patient, the quantity and frequency of administration will ultimately be at the discretion of the attendant physician. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1,2,3 or 4 puffs each time. The preferred treatment regime is 1 or 2 puffs of 25, 50, 125 or 250 xcexcg/puff fluticasone propionate, 2 times per day.
The filled canisters and metered dose inhalers described herein comprise further aspects of the present invention.
A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of a formulation herein before described,
A further aspect of the present invention comprises the use of a formulation herein before described in the manufacture of a medicament for the treatment of respiratory disorders, eg. asthma or chronic obstructive pulmonary disease (COPD).
As mentioned above the advantages of the invention include the fact that formulations according to the invention may be more environmentally friendly, more stable, less susceptible to Oswald ripening or drug deposition onto internal surfaces of a metered dose inhaler, have better dosing uniformity, deliver a higher FPM, give lower throat deposition, be more easily or economically manufactured, or may be otherwise beneficial relative to known formulations.
The invention is illustrated with reference to the following examples: